Nonlinear response surface in the study of interaction analysis of three combination drugs.

Few articles have been written on analyzing three-way interactions between drugs. It may seem to be quite straightforward to extend a statistical method from two-drugs to three-drugs. However, there may exist more complex nonlinear response surface of the interaction index (II) with more complex local synergy and/or local antagonism interspersed in different regions of drug combinations in a three-drug study, compared in a two-drug study. In addition, it is not possible to obtain a four-dimensional (4D) response surface plot for a three-drug study. We propose an analysis procedure to construct the dose combination regions of interest (say, the synergistic areas with II≤0.9). First, use the model robust regression method (MRR), a semiparametric method, to fit the entire response surface of the II, which allows to fit a complex response surface with local synergy/antagonism. Second, we run a modified genetic algorithm (MGA), a stochastic optimization method, many times with different random seeds, to allow to collect as many feasible points as possible that satisfy the estimated values of II≤0.9. Last, all these feasible points are used to construct the approximate dose regions of interest in a 3D. A case study with three anti-cancer drugs in an in vitro experiment is employed to illustrate how to find the dose regions of interest.